Noretiocholenic acids and process



OC- 30, 1951 M. R. EHRENSTEIN NoRETIocHoLENIc ACIDS AND PROCESS Filed Nov. 2, 1950 O Y m INVENTOR. MA x/M/L/AN R. EHREA/sTf/N ATTORNE Patented Oct. 30, 1951 NORETOCHGLENIC ACIDS AND PROCESS Maximilian R. Ehrenstein, Philadelphia, Pa., as-

signor to The Trustees of the University of Pennsylvania, Philade of Pennsylvania lphia, I'a.,v a corporation Application November 2, 195o, serial No. 193,693

More specifically, the new chemical compounds contemplated by this invention will include the new compound l-norprogesterone,A related compounds and various intermediates, which are produced in the course of its preparation by the method according to this invention.

The new com-pounds,10norprogesterone and related compounds, have been found .to have progestational activity rendering them useful therapeutically in the endocrine eld. The new compounds comprising intermediates formed 'in the course of preparation of lnorprogesterone will find utility in connection with the prepara.- tion of -norprogesterone and variously may be found to have therapeutic value.

- The particular structureofv the new compound, lO-norprogesterone, and the structure of .the novel compounds comprising intermediates formed in the preparation of l0-norprogesterone and the procedure according tothe method of this invention is illustrated in the scheme shown in the accompanying drawing, with reference lto A The formulae illustrate the structures of 10-V yIIS norprogesterone and of the several intermediates scribed, for example, by Butenandt and Gal-V lagher, Ber. 72, p. 1866 (1939); Chem. Abstr. 34 s Proceeding now according to the method `of this invention, as indicated in the scheme, the compound B is formed by acylation of the starting compound A to protect the hydroxyl group y (Cl. 26o-397.1)

2 water bath for about one hour. On completion of the heating the;solvent is removed in vacuo C.) and the sirupy residue taken up in ether and the solution extracted twice with ice cold dilute sodium carbonate. The combined extracts are acidied by addingv without delay iceY cold dilute hydrochloric acid which will cause a white nocculent precipitate to appear. The suspension is then extracted three times with ether and the combined ether extracts washed several times with small quantities of water. After drying and filtering, evaporation of the ether yields a product, usually obtained as a .foamy, colorless glass. This product, which comprises the compoundB, is then, for analysis, dried at 85 C. under slight vacuum in order to avoid possible decomposition and analyzes as follows:

Calculated for C22H32Ov monoacetate): C,64.66; H,'7.90. Found: 0,6420; II,'7.36. f

Proceedingnow fromthe compound'B tothe compound C, which, for example, may be 3-acetoxy-lo-noretiocholenic' acid (3-acetoxy estrene-l7-carboxylic acid), the compound'B is subjected to heating in ahigh vacuum to effect dehydration and decarb'oxylation of the compound B. 'Preferably the compound B will be subjected to distillation" in a high vacuum.

As exemplifying the'procedure for the prepara; tion of compound C from the compound B, where the compound Bis, for example, an acetate, 0.590 g. of the crude compound B is transferred into a high vacuum retort by means of ether. After careful removal of the solvent, a foamy glass remains, which, on gentle heating in a high vacuum to a temperature of -l20 C., is almost completely liquefied or sintered. The material thus obtained, essentially free from solvent is subjected to distillation in a high vacuum. In effecting the distillation the temperature is raised fairly quickly to about 180 C. where gas evolution will be observed. Subsequently, the temperature is raised slowly, say within a period of `about one hour, at 250 C. and then quickly raised to about 290 C. and the distillation thereafter at carbon atom 3. The acylation of the compound A is, for example, effected by treatment with an acid anhydride, as, for example, acetic anhydride, propionic anhydride, or othersuitable anhydride which will protect the hydroxyl group at carbon atom 3.

' As exemplifying the procedure for acylation of the compound A, using acetic anhydride, a solution of 0.450 g. of recrystallized estrane3,5diol 10,17-dicarboxylic acid in 4.5 cc. of acetic anhydride is reuxed (metal-bath, -l50 C.) for 30 minutes, after which 4.5 cc. of glacial acetic acid and 2.7 cc'. of water are added to decompose anhydrides and the solution then heated Qll. al

interrupted. The distillate, usually a slightly yellow, brittle glass, is subjected to another dis- 1 tillation under practically identical conditions, it

being noted that in the redistillation there is no notable gas evolution. The product usually is a slightly yellow, brittle glass and gives a strong positive reaction with tetranltromethane. Analysis shows the following: f -V Calculated for (121143004: C,72.78, H873. Found: C,73.36,.72,78; II,8.30, 8.51.

Titration: 11.2 mg. of the product required v3.31 cc. of 0.01 N NaOI-I; calculated for mono carboxylic acid C21H3o04; 3.23 cc.

In this product as4 illustrated in the scheme the double bond may be in the 5,6position, the.'5,10 position, or in the 4.5 position, or the product may be a mixture of any two or all of these for example, may be .Y

3-acetoxy 10 noretiocholenic .acid Tchloride s (3-acetoxyestrene-l7-carboxylic acid chloride) and/or isomers, the compound C fis .':directly transformed into the correspondingacid chloride and/ or isomers by means ofrforfexample,--th1onyl chloride, phosphorous oxychloride or phosphorous pentachloride. It willfbellndelstoodthat the compound D may be prepared as an acid bromide by using an equivalent bromidein-plaee of the aforementioned chlorides.

. .'-As .exemplifying .the procedurefforthe preparation ofthe compound FDfrom the compound C, a purified, colorless :fthionyl chloride is prepared, for example, '-i'by distilling pure commercial thionyl chloride Eastman),of .a slightly yellow color, over quinolinefand .then over "linseed Ioil. T0200 mg. of ."the.l compound `C, and/or isomers, isfadded in .a cold -room"1:0cc. of the purified thionyl chloride. .The mixture is allowed to stand under anhydrous conditions inthe cold room (about/2 C.) 'for a period of about 50 minutes and `then atV room temperature (201CL) for about ."31/2 hours, whichusually results the formationfof an olive .green solution. The solution vthus #formed isbrought :to Ydryness invacuo (40 C.) under .anhydrous conditions. TheA residue is then dried overnightfin a vacuum desicc'aitor (P2O.=,,K'OH)l The acid chloride, .or :theebromidefthus preparedI servesfor the production ofthe compound E; as.^for example, s3eacetoxylenorpregnene- 20,-oneiand/or isomers.

The 'compound fD, .or zrelated v'compounds Aindicated above .andi/oriisomers,fisv ofyaluemot only as anvintermediate cfon-the fpreparation of the novel eompound'l-Ufnorprogesterone according to the method of this*inventiongbutlikewise usefulfor lthe `preparation Yof the -fn'ovel compound nor -'11 desoxycorticosterone acetate, and which novel compoundvtogether with 1various intermediates :usefulfferite-*preparation and vmeth-- ,odgfor the preparationthereon` forms the subject'- As exempliiying procedure for transforming,

forfexample, thecompoundDto, for-example, the

compound `E, a fuming, colorless solution of methylzinc iodide is prepared by adding a zinc- Y copper couple, prepared from 2 g. of zinc (zinc reagent-r-Merck,`Mossy cut in small pieces 1-3 mm. size) and 0.2 g. of copper powder, by the method. ofilobland` Reich, Bull. Soc. Chim. [4].

'33,314.14 (11923), and an iodine crystal to a mixrturchi-2.33Vg. ofmethyl iodide (Eastman, pure),

0.5 cc. of dry alcohol-free ethyl acetate, and '1.0

jlcc.ofvdry toluene.- The mixture was heated (reflux condenser) under anhydrous conditions in l'a metalbath to 80 C. Over a period of 11/2 hours compound D,prepared from-200 mg. of -compound'C, in 1.0 ce. ofdrybenzene is slowly added. The mixture is allowed to `standat-room vtemperature (24 C.) for about'30minutes. After cooling with ice,l water is graduallyvadded, whichresults in the formation of a thiol: precipitate which is brought'into -solutionf-byl adding an lexcess of Nsulfuric acid `until acid to Congo. 1The reactionmixture isfthen extracted with an-ample quantity of etherand the-ether extractwashed with a concentrated solutionfof ammonium sulfate, Water, a solution of N sodium hydroxide and then threey times with `small lquantities of lWater (neutral Vether extract) The neutral etherfextractisdriedwith sodium sulfate, brought to dryness'rin vacuo (40 C.) and the 'residue dried in Va 'vacuum desiccator (P2O5;KOH). The residuefis usually an orangecolored viscous oil, amounting Yto about 135 mg.

The neutral residue'issub'jected to chromatof graphic adsorption by `dissolving lit in a mixture of 10 cc. of benzene an'df25cc. ofpetroleum' ether and subsequently filtering through a column of 6.0 g. of aluminumroxide. The original solution is passed through Withinabouttwohours and the eluates eachfwithinlS minutes. The following fractionation'is obtained.

No of A l Weght'o Y s .Frin Solvent fReAsguc, vpmamnce oLResldue 10 cc. Benzene+25 cc. petr. 13.10 colorless sticky oil.

other (original solution). 6 cc.benzcne+14 capetr. ether; 46. l slightly `yellow sticky'oil. Rec. benzene-k12 ce. petr. ether 21. 1 colorless resin. i0 ten. benzene-H0 cc. petr. 11.4 Do.

e er. 13 co.,be11zenelf7 ce. petr. ether. 6. 8. f Do. 17 cc.benzene+3 cerpetr. ether. 5. 9 Do. 20 ce. benzene 4. 6 Do. do 2. 3 Do. 17 ce. benzene-P3 ce. ether 4. 2 Do. T13 cc. benzene-H cc.\ether V 1.9 Do. 10 cc. benzene-H0 cc. ether 1.0r D0.

5 cc. benzene-H5 cc. ether- '0. 5 20 cc..ether 0:4

d 1.1'r colorless resin. l. -6. 4 yellow resin.

30 camethsnol '10.-',61 whitish-bitownishrcsidue.

Total 137.3

matter of an application -ffor patent lel by me Serial No. 25,824.1iled May 0,1948. K

The preparationof the compound E, or related compounds indicated above-andf/or isomers, from the compound Dis -accomplished by treatment of the compound D or related compounds indicated *above and/or isomers with a Amethylzincl halide, preferably methylzinc iodide or with dimethyl cadmium.

Fractions 2-8, inclusive of the chromatogram (98.2 mg.) are combined andsubjected .to adistillation in high vacuum, heating to C. Within 10 minutes and gradual raising of .the temperature to slightlyabove @20.0 C. within `a period O f One h our, whhyields about .87.5 mg.

The majo;` part of thedistillate `(76.8 mg.) .is subjected to further purification by means of Girards reagent y'Jl (betaine ,hydrazide 4hydrochloride) by the addition of 110 mg. of Girards reagent and 0.06 cc. of glacial acetic acid to the distillate dissolved in 1.0 cc. of methanol and reiiuxing on a water bath for 1 hour and then allowing to stand in the cold room for two days.

twice with ether in the cold room and the combined ether phases washed at room temperature successively with water, a solution of N sodium carbonate and four times with water. After drying with sodium sulfate and removal of the ether, an almost colorless resin is usually obtained (non-ketonic fraction).

The aqueous phase is then made acid to Congo by adding 1 cc. of 4 N sulfuric acid in the cold room and the resultant mixture extracted four times with ether at room temperature and the combined ether phases washed successively with water, a solution of N sodium carbonate and four times with water. After drying the ethereal solution with sodium sulfate and subsequent removal of the ether an almost colorless, soft resin (ketonic fraction) is usually obtained. An additional amount of the ketonic fraction can be obtained by subjecting the non-ketonic fraction above to treatment with Girards reagent under the conditions indicated above. 30

The almost colorless, soft resin (ketonic fraction: about 47.4 mg.) obtained above is subjected to distillation in a high vacuum, yielding as the distillate usually a slightly yellow, viscous resin which comprises the compound E and/or isomers.

The preparation of the compound F, 10-norether, usually an amber colored resin comprising the compound F is obtained.

The preparation of l-norprogesterone (compound G) from the compound F and/or isomers is accomplished by dehydrogenation of the compound F using, for example, the method described by Oppenauer Rec. Trav. Chim. 56, 137 (1937), though other suitable methods for dehydrogenation may be used.

As exemplifying procedure for transforming the compound F to the compound G, to 4 cc. of a clear solution of about 100 m'g. of aluminum tert.butoxide (Eastman) in 1.0 cc. of dry benzene is added about 29.7 mg. of the compound F dissolved in 1.2 cc. of dry acetone. The resulting solution is reluxed under anhydrous conditions on a water bath for a period of 10 hours, during which time an additional 0.2 cc. of dry acetone is added. The solution is permitted to stand at room temperature overnight, then an ample amount of ether and thereafter some'N sulfuric acid are added to the solution. The ether phase is separated and washed with a dilute solution of sodium bicarbonate and three times with water. After drying with sodium sulfate and removal of the ether a yellowish, soft resin is usually obtained amounting to about 30.4 mg.

The resin thus obtained is purified by chromatographic adsorption by dissolving it in a mixture of 7.5 cc. of benzene and 22.5 cc. of petroleum ether and by subsequently filtering said solution through a column of 2.0 g. of aluminum oxide during a period of about three hours, the eluents being passed through each over a period of 30 minutes. The following chromatographic fractionation is obtained.

Weight of No. of Appearance of Resi- Fraction Solvent Rehsgue due l 7.5 cc. benzene+22-5 cc. petr. ether 1.9 colorless resin.

(original solution).

2 2.5 cc. benzene-|75 cc. petr. ether.. 0.6 colorless residue.

3.. 3.5 cc. benzene-Hij cc. petr` ether. 0.2 Do.

4.- 5 cc. benzene-Hi cc. petr. ether.. 1.4 Do.

5-. 7 cc. benzene-HJ, cc. petr. ether..- 4. 3 colorless resin.

6 9 ce. benzene-H cc. petr. ether.. 4.1 Do.

7-- l0 cc. benzene 2. 2 Do.

8-- -do 0.9 D0.

9-- 8 cc. benzene-F2 cc. ether. 2.4 colorless glass.

l0- 6 cc. benzene-F4 cc. ether. 0. 6 colorless residue.

l1- 4 cc. benzene-F6 cc. ether. 1.7 colorless resin.

l2 l0 cc. ether 2.1 o.

13. do 0. 2 Do.

14. 7.5 cc. ether-$2.5 cc. methanol 5. 4 light yellow glass.

15. l0 cc. methanol 3. 0 whitish mass.

Total 31.0

pregnene-20-one-3-ol, and/or isomers, from the 55 compound E or related compounds indicated above and/or isomers, is accomplished by hydrolysis, preferably under alkaline conditions, of the compound E to replace the acyloxy group at carbon atom 3 with a hydroxyl group. 50 As exemplifying procedure for the hydrolysis of, for example, the compound E, 3-acetoxy-l0- norpregnene-ZO-one and/or isomers, to 39.2 mg. of the compound E, dissolved in 1.0 cc. of methanol is added a solution of 0.1 g. of potases sium carbonate in 0.5 cc. of water and l cc. of methanol. The mixture is refluxed on a water bath for 11/2 hours and is then made acid to Congo by the addition of dilute hydrochloric acid. The major part of the methanol is then 70 removed in vacuo C.) and the mixture extracted with ether. The ether phase is washed with a little water, a solution of N sodium carbonate and three times with water. After drying with sodium sulfate and evaporation of the '(5 max=238.5 my.; 6:16560 By reference to the scheme shown in the drawing it will be appreciated that from the broad standpoint this invention is not limited in the case of compounds D, E, F and G to compounds having the grouping COCl or COCI-k at carbon atom 17, but to the contrary contemplates also those compounds having the structure'of compound D except lfor the fact that they have the grouping COX at carbon atom 17, where X is chlorine or bromine, and also those compounds having the structure of compounds E, F and G except for the fact that they have the grouping COR yat carbon atom 17, where R is -an Valkyl group, an aryl group or an aralkyl group and, more specifically, where R is an alkyl'group containing not more than five carbon atoms.

The compounds having the grouping COR at carbon atom 17 may be formed by treating the compound D to form the compound E as described above except `for the use of an alkyl, aryl or aralkyl zinc halide or a dialkyl, diaryl or diaralkyl cadmium in place of a metal zinc'halide or dimethyl cadmium.

The compounds C-E, inclusive, according'to this invention, will more particularly have the grouping RO at carbon atom 3, whereR is an aliphatic or aromatic acyl group, for example, a benzoyl group, a phenyl acetyl group or an aliphatic acyl group having 2-6 carbon atoms, as a propionic group, a butyric group, a valerie group Or a Paroic group.

The compounds having vRC at carbon atom 3, respectively, Will be formed as described above by acylation of compound A using the reagent corresponding to the desired substituent for R in place of acetic anhydride, it being apparent that the OH group at carbon atom 3 in compound A is highly reactive. Alternatively, a chloride instead of an anhydride may be used to introduce the desired group R.

Specific examples of the compounds according to this invention Where the grouping COR' at carbon atom Il and the grouping RO at carbon atom 3 are as given above specically will be obvious and will be had by substitution in the structural formulae shown in the vattached scheme of respectively the several substituents given for R.

It will be understood, with reference to the several compounds illustrated and vdescribed above, that I do not intend that -thisnvention or the claims appended hereto shall be limited to any particular configuration about any carbon atom and, in particular, about carbon atoms '3, 10, 14 and 17.

This application is a continuation-:impart ofmy application Serial No, 28,033, filed May 19, 1948 (now abandoned), which is a continuationin-part of my application Serial No. 647,967, filed February 15, 1946 (now abandoned), 'which is a division of my `,application Serial No. 584,623, led March 24, 1945 (now abandoned).

What is claimed is:

1. A 13-monomethyl cyclopentanopolyhydrophenanthrene having the following structure:

BO 3 --A=a carbon to carbon double bond \//5\6/ extending vfrom vcarbonatom z5 where R is an aliphatic acyl group havingl 2;-6

carbon atoms. 2. A 13-monomethyl -cyclopentanopolyhydro phenanthrene having the following Structure:

l--A=a carbon to carbon double bond 6/ extending from carbon atom 5 where R is amember of the group consisting of aliphatic acyl groups having 2-6 carbon atoms, a benzoyl group and a phenyl acetyl group, which comprise acylating at vcarbon atom .3 a compound having the following structure:

O 17 H HO-C 14 (n How and simultaneously dehydrating and decarboxylating the acylation product by heating in vacuo. 4. The steps in the process of preparing a l-'monomethyl cyclopentanopolyhydrophenanthrene having the following structure:

COOH

5`\6/ extending from carbon atom 5 where R. isa member of the group consistingof aliphatic acyl -groups having 2-6 carbon atoms, a benzolyl group and a phenyl acetyl group, which comprise reuxing a compound having the fol-'- lowing structure:

20 C 0 OH 0 17 ll HO-C 14 with an acyl anhydride and heating the product thereof in vacuo` MAEHMILIAN R. EHRENSTEIN.

No references cited. 

1. A 13-MONOMETHYL - CYCLOPENTANOPOLYHYDROPHENANTHRENE HAVING THE FOLLOWING STRUCTURE: 